Drug addiction is a brain disorder having enormous costs on society, yet effective treatments have not been elucidated. The rewarding properties of drugs of abuse contribute to initial drug taking behaviors that over time form an addiction that is characterized by increasing drug consumption and increasing susceptibility to relapse during periods of abstinence. The primary goal of the studies in this application is to enhance our understanding of the pharmacological mechanisms involved in cocaine reward and relapse that may aid in the development of more effective treatments. Chronic or repeated drug use results in several enduring perturbations in the brain circuitry that regulate motivated behavior prompting relapse in addicts. The nucleus accumbens (NAc) is a brain structure known to regulate behaviors associated with addiction (i.e. drug self-administration, relapse and reward) in both humans and rodents. Within the nucleus accumbens, subtypes of dopamine (D1 and D2) and adenosine receptors (A1 and A2A) modulate neuronal activity in a complementary, yet opposing manner. The interplay between these receptors and their subtypes is intriguing because they are: 1) localized to distinct populations of NAc neurons and 2) play reciprocal roles on the activity of adenylyl cyclase, an intracellular enzyme mediating cellular activity. It remains unclear how this reciprocal activity at the cellular level translates to the behavioral level, especially in the context of addiction. Preliminary findings demonstrate that stimulation of adenosine A2A receptors with systemic administration of A2A receptor agonists reduces relapse to cocaine seeking. Therefore, the overriding hypothesis for this application is that dopamine actions in the NAc that induce relapse will be tempered by increasing the reciprocal adenosine system in the NAc. Aim 1 will evaluate effects of 1) elevating endogenous adenosine levels and 2) directly stimulating NAc adenosine A2A receptors on the cocaine reward using a place-conditioning paradigm and cocaine reinforcement using a progressive-ratio self- administration paradigm. Aim 2 will identify the effects of 1) elevating endogenous adenosine levels and 2) directly stimulating NAc adenosine A2A receptors on cocaine relapse following chronic cocaine self- administration. Together these studies will provide a foundation for future work to identify the molecular mechanisms associated with the reciprocity of dopamine and adenosine receptors within NAc that contribute to cessation of cocaine use. PUBLIC HEALTH RELEVANCE: Drug addiction is a serious mental illness that involves significant motivational disturbances resulting in a loss of behavioral control leading to destruction of the afflicted individual as well as their surrounding social networks. This disease affects millions of people and generates enormous social and economic costs to society. The goal of this research is to better understand the disease as a whole, identify specific strategies to reduce cocaine use and evaluate major biological targets for potential therapeutic intervention to promote abstinence.